Characteristics of participants of subjects
In the present study, 2773 pregnant women without preconceptional diabetes were involved, with a mean age of 31.50±3.93 years and mean prepregnancy BMI of 21.00±3.21 kg/m2. The mean value of fasting serum total bile acid concentrations at the second trimester was 2.57±1.58 (µmol/L). During this prospective study, 652 of 2773 (23.51%) women developed GDM. As shown in Table 1, compared with the Non-GDM group, subjects in the GDM group had older age, higher prepregnancy BMI levels, as well as higher levels of uric acid, total bilirubin, creatinine, TG, fasting insulin, 1-and 2-h post-load insulin, fasting plasma glucose, 1-and 2-h post-load glucose, HbA1c and HOMA-IR (all P < 0.05). Interestingly, serum total bile acid levels were increased in women in the GDM group compared with those in the Non-GDM group (2.98 ± 1.15 vs. 2.37 ± 1.33 µmol/L, P < 0.001) (Table 1).
Table 1
Baseline characteristics of participants with and without GDM: demographics and laboratory values
| Serum TBA level (µmol/L) |
| Total | Non-GDM | GDM | P for trend |
N | 2773 | 2121 | 652 | |
Age (years) | 31.50±3.93 | 31.24 ± 3.89 | 32.37 ± 3.94 | ༜0.001 |
BMI, kg/ m2 | 21.00±3.21 | 20.67±3.18 | 22.07±3.06 | ༜0.001 |
< 24 | 2503 | 1990 | 513 | ༜0.001 |
≥ 24 | 270 | 139 | 131 | |
Education background (n, %) | | | | 0.028 |
High School and Below | 629 (22.68%) | 490 (23.10%) | 139 (21.32%) | |
Junior College | 674 (24.31%) | 490 (23.10%) | 184 (28.22%) | |
University | 1470 (53.01%) | 1141 (53.80%) | 329 (50.46%) | |
Smoking Status | | | | 0.997 |
Current smoker | 68 (2.45%) | 52 (2.45%) | 16 (2.45%) | |
Nonsmoker | 2705 (97.55%) | 2069 (97.55%) | 636 (97.55%) | |
Drinking Status | | | | 0.823 |
Current drinker | 69 (2.49%) | 52 (2.45%) | 17 (2.61%) | |
Nondrinker | 2704 (97.51%) | 2069 (97.55%) | 635 (97.39%) | |
Blood pressure (mmHg) | | | | |
SBP (mm Hg) | 117.05±12.10 | 116.82 ± 12.04 | 117.76 ± 12.45 | 0.086 |
DBP (mm Hg) | 66.84±9.14 | 66.72 ± 9.07 | 67.24 ± 9.33 | 0.199 |
Serum TBA level (µmol/L) | 2.57±1.58 | 2.37 ± 1.33 | 2.98 ± 1.15 | ༜0.001 |
Glucose metabolism | | | | |
Fasting plasma insulin (µU/ml) | 5.11±2.09 | 8.26±2.38 | 4.20±0.58 | ༜0.001 |
1-h post-load insulin (µU/ml) | 67.80±3.96 | 70.30±4.07 | 54.87±3.30 | ༜0.001 |
2-h post-load insulin (µU/ml) | 46.18±3.87 | 34.87±2.84 | 49.89±2.93 | ༜0.001 |
Fasting plasma glucose (mmol/L) | 4.62±0.38 | 4.53±0.29 | 4.91±0.47 | ༜0.001 |
1-h post-load glucose (mmol/L) | 8.36±1.82 | 7.56±1.32 | 9.80±1.69 | ༜0.001 |
2-h post-load glucose (mmol/L) | 7.08±1.51 | 6.48±0.98 | 8.58±1.55 | ༜0.001 |
HbA1c (%) | 5.14±0.53 | 4.92±0.44 | 5.25±0.53 | ༜0.001 |
HOMA-IR | 1.06±0.50 | 2.13±4.7 | 1.19±0.7 | ༜0.001 |
Lipid profile | | | | |
TC (mmol/L) | 5.31±0.88 | 5.56 ± 0.68 | 5.23 ± 0.93 | 0.196 |
TG (mmol/L) | 2.11±0.65 | 1.93 ± 0.67 | 2.17 ± 0.65 | 0.011 |
HDL-C (mmol/L) | 1.67±0.30 | 1.78 ± 0.28 | 1.63 ± 0.31 | 0.022 |
LDL-C (mmol/L) | 2.69±0.85 | 2.55 ± 0.83 | 3.06 ± 0.85 | 0.075 |
Liver function | | | | |
ALT (units/L) | 17.80±3.87 | 17.54±3.45 | 18.60±5.05 | 0.164 |
AST (units/L) | 18.14±4.69 | 18.21±7.53 | 17.94±8.17 | 0.527 |
Uric acid (µmol/L) | 210.86±44.20 | 209.11±43.30 | 216.32±46.39 | 0.003 |
Total bilirubin (µmol/L) | 7.44±2.78 | 7.14 ± 2.84 | 7.53 ± 2.75 | 0.009 |
Direct bilirubin (µmol/L) | 2.39±1.42 | 2.47 ± 1.59 | 2.24 ± 0.98 | 0.106 |
Urea nitrogen (mmol/L) | 2.60±0.63 | 2.60 ± 0.64 | 2.59 ± 0.58 | 0.607 |
Creatinine (µmol/L) | 43.46±6.79 | 42.48 ± 6.56 | 43.77 ± 6.84 | 0.001 |
Maternal characteristics | | | | |
Gestational age at delivery (weeks) | 38.68±1.61 | 38.73±1.63 | 38.02±1.52 | 0.003 |
Nulliparous (n,%) | 1160 | 873 (41.16%) | 287 (44.02%) | 0.196 |
Abortion history (n,%) | 1089 | 808 (38.10%) | 281 (43.09%) | 0.022 |
PROM (%) | 607 | 471 (22.21%) | 136 (20.86%) | 0.467 |
Preeclampsia (n,%) | 107 | 67 (3.16%) | 40 (6.13%) | 0.001 |
Premature birth (n,%) | 177 | 131 (6.17%) | 46 (7.06%) | 0.002 |
Postpartum hemorrhage (mL) | 211.60±129.82 | 212.58±140.71 | 208.42±85.19 | 0.475 |
Offspring | | | | |
Weight (g) | 3287.80±481.92 | 3288.53±486.05 | 3285.44±468.60 | 0.886 |
Macrosomia (n,%) | 199 | 159 (7.50%) | 40 (6.13%) | 0.239 |
Height (cm) | 49.84±1.90 | 49.85±1.95 | 49.81±1.74 | 0.040 |
Head circumference (cm) | 33.95±1.63 | 33.95±1.48 | 33.92±2.04 | 0.607 |
Chest circumference (cm) | 33.20±2.08 | 33.22±1.97 | 33.12±2.43 | 0.262 |
Data represent means ± SD or percentage (%). |
Significant difference if P < 0.05 |
GDM, gestational diabetes mellitus; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TBA, total bile acid; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TC, total cholesterol; TG, total triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycosylated hemoglobin; HOMA-IR, homeostasis model assessment of insulin resistance index. |
Moreover, there were differences between GDM and Non-GDM groups in gestational age at delivery and abortion history, as well as the birth height of the fetus. GDM women tend to develop preeclampsia (6.13% vs. 3.16%, P = 0.001) and premature birth (7.06% vs. 6.17%, P = 0.002) (Table 1). However, significant differences were not found in the occurrence of premature birth, PROM and macrosomia between two groups (All P> 0.05).
Serum TBA Levels Were Associated with an Increased Risk of GDM
To further investigate the associations of serum TBA levels at the second trimester with GDM, the individuals were categorized according to quartiles of serum TBA levels. As shown in Table 2, the levels of fasting insulin, 1-and 2-h post-load insulin, fasting plasma glucose, 1-and 2-h post-load glucose, HbA1c and HOMA-IR and serum TG were elevated by increasing serum TBA quartiles (all P < 0.05), whereas the level of HDL-C reduced by increasing serum TBA quartiles (P = 0.033). Then, we explored the correlation between TBA levels and some metabolic risk factors. Serum TBA levels were correlated with age, prepregnancy BMI, fasting plasma glucose, 1-and 2-h post-load glucose levels, HbA1c, HOMA-IR, TG, BUN, CRE, AST and ALT levels (All P < 0.05, Additional File 1). Additionally, elevated serum TBA levels at were associated with an increased occurrence of preeclampsia and premature birth in a dose-response manner (Table 2).
Table 2
Baseline characteristics of participants according to quartiles of serum TBA levels
| Serum TBA level (µmol/L) | |
| Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 | P for trend |
Serum TBA level (µmol/L) | < 1.60 | 1.60–2.20 | 2.20–3.11 | ≥ 3.11 | |
Participants, n | 664 | 647 | 768 | 694 | |
Age (years) | 31.53±3.89 | 31.46 ± 3.99 | 31.36 ± 3.77 | 31.67 ± 4.01 | 0.487 |
BMI, kg/ m2 | 20.68±2.50 | 20.95±3.95 | 21.05±3.02 | 21.29 ± 3.23 | 0.006 |
< 24 | 621 | 599 | 687 | 596 | ༜0.001 |
≥ 24 | 43 | 48 | 81 | 98 | |
Smoking Status | | | | | 0.992 |
Current smoker | 16 (2.41%) | 16 (2.47%) | 18 (2.34%) | 18 (2.59%) | |
Nonsmoker | 648 (97.59%) | 631 (97.53%) | 750 (97.66%) | 676 (97.41%) | |
Drinking Status | | | | | 0.932 |
Current drinker | 15 (2.26%) | 17 (2.63%) | 18 (2.34%) | 19 (2.77%) | |
Nondrinker | 649 (97.74%) | 630 (97.37%) | 750 (97.66%) | 676 (97.41%) | |
Blood pressure (mmHg) | | | | | |
SBP (mm Hg) | 117.26±12.14 | 116.90 ± 11.64 | 116.66 ± 11.99 | 117.40 ± 12.74 | 0.554 |
DBP (mm Hg) | 66.72±8.92 | 66.87 ± 8.60 | 66.79 ± 9.06 | 66.99 ± 9.91 | 0.112 |
Glucose metabolism | | | | | |
Fasting plasma insulin (µU/ml) | 6.85±1.76 | 7.20±3.00 | 8.87±4.65 | 9.15±1.55 | ༜0.001 |
1-h post-load insulin (µU/ml) | 55.03±2.90 | 58.52±1.43 | 66.52±3.93 | 67.67±3.35 | ༜0.001 |
2-h post-load insulin (µU/ml) | 36.30±4.17 | 47.86±3.80 | 48.05±4.01 | 51.84±3.29 | ༜0.001 |
Fasting plasma glucose (mmol/L) | 4.54±0.33 | 4.62±0.40 | 4.63±0.36 | 4.68±0.42 | ༜0.001 |
1-h post-load glucose (mmol/L) | 7.94±1.68 | 8.18±1.79 | 8.28±1.59 | 8.99±2.00 | ༜0.001 |
2-h post-load glucose (mmol/L) | 6.75±1.26 | 6.87±1.33 | 7.21±1.50 | 7.42±1.77 | ༜0.001 |
HbA1c (%) | 5.01±0.40 | 5.14±0.81 | 5.18±0.40 | 5.20±0.52 | 0.005 |
HOMA-IR | 1.06±0.50 | 2.13±4.7 | 1.19±0.7 | | ༜0.001 |
Lipid profile | | | | | |
TC (mmol/L) | 6.29±0.30 | 5.27 ± 1.23 | 5.12 ± 0.83 | 5.26 ± 0.66 | 0.233 |
TG (mmol/L) | 1.87±0.64 | 2.05 ± 0.74 | 2.32 ± 0.54 | 2.66 ± 0.08 | 0.024 |
HDL-C (mmol/L) | 1.59±0.38 | 1.67 ± 0.30 | 1.71 ± 0.33 | 2.03 ± 0.22 | 0.033 |
LDL-C (mmol/L) | 2.65±0.86 | 2.89 ± 1.13 | 2.59±0.82 | 2.62±0.70 | 0.825 |
Liver function | | | | | |
ALT (units/L) | 16.30±1.25 | 18.38±1.52 | 17.80±1.35 | 18.72 ± 1.41 | 0.053 |
AST (units/L) | 17.39±6.81 | 18.48±8.08 | 18.09±7.74 | 18.64 ± 8.03 | 0.075 |
Uric acid (mmol/L) | 212.23±45.12 | 220.83±44.65 | 208.39±41.82 | 212.42±45.38 | 0.470 |
Total bilirubin (µmol/L) | 7.42±2.59 | 7.40 ± 2.70 | 7.47 ± 2.89 | 7.45±2.90 | 0.975 |
Direct bilirubin (µmol/L) | 2.53±1.20 | 2.28 ± 1.04 | 2.20 ± 1.06 | 2.57 ± 2.01 | 0.436 |
Urea nitrogen (mmol/L) | 2.62±0.63 | 2.58 ± 0.64 | 2.59 ± 0.64 | 2.60 ± 0.62 | 0.854 |
Creatinine (µmol/L) | 43.80±6.75 | 43.36 ± 6.86 | 43.31 ± 6.59 | 43.37 ± 7.01 | 0.676 |
Maternal characteristics | | | | | |
Gestational age at delivery (weeks) | 38.76±1.58 | 38.74±1.48 | 38.71±1.63 | 38.50±1.74 | 0.012 |
Nulliparous (n,%) | 237 (35.69%) | 309 (47.76%) | 298 (38.80%) | 315 (45.53%) | 0.005 |
Abortion history (n,%) | 263 (39.61%) | 296 (45.75%) | 279 (36.33%) | 251 (36.17%) | 0.213 |
PROM (%) | 125 (18.83) | 147 (22.72%) | 158 (20.57%) | 136 (25.50%) | 0.177 |
Preeclampsia (n,%) | 17 (2.56%) | 18 (2.78%) | 33 (4.30%) | 39 (6.13%) | ༜0.001 |
Premature birth (n,%) | 27 (4.07%) | 33 (5.10%) | 60 (7.81%) | 57 (8.21%) | 0.003 |
Postpartum hemorrhage (mL) | 214.44±173.16 | 207.50±106.04 | 210.22±103.46 | 214.25±128.22 | 0.721 |
Offspring | | | | | |
Weight (g) | 3247.15±502.40 | 3313.83±457.40 | 3178.99±488.25 | 3287.80±481.92 | 0.887 |
Macrosomia (n,%) | 36 (5.42%) | 48 (7.42%) | 60 (7.81%) | 55 (7.93%) | 0.096 |
Height (cm) | 49.66±2.20 | 49.93±1.71 | 49.84±1.96 | 49.84±1.90 | 0.021 |
Head circumference (cm) | 33.84±1.59 | 34.06±1.53 | 33.93±1.48 | 33.95±1.90 | 0.133 |
Chest circumference (cm) | 33.12±2.25 | 33.26±2.08 | 33.19±1.84 | 33.22±2.17 | 0.643 |
Data represent means ± SD or percentage (%). |
Significant difference if P < 0.05 |
GDM, gestational diabetes mellitus; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TBA, total bile acid; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TC, total cholesterol; TG, total triglycerides; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycosylated hemoglobin; HOMA-IR, homeostasis model assessment of insulin resistance index. |
Then we performed binary logistic regression with the first quartile of serum TBA levels (< 1.60 µmol/L) as a reference to further assess the association between TBA levels and the risk of GDM in a series of adjusted models. Table 3 revealed that higher serum TBA quartile was associated with higher odds of GDM (the highest tertile vs. the lowest tertile, AOR 2.30, 95% CI 1.62–4.25, P < 0.001) after adjusting for age and BMI. Furthermore, these associations still maintained robustness after the adjustment for related factors in Multivariable model 2 and 3. After adjusting for the variables of age, BMI, smoking and drinking status, education background, systolic blood pressure, diastolic blood pressure, TC, TG, LDL-C, HDL-C, ALT, AST, uric acid, total bilirubin, direct bilirubin, urea nitrogen and creatinine, the ORs of GDM in Model 3 for the highest (vs. the lowest) quartile were 1.83 (95% CI 1.10–3.38) in women.
Table 3
Odds ratios (95% confidence intervals) of baseline serum TBA levels on the risk of GDM.
| Serum TBA Level (µmol/L) | |
| Quartile 1 (< 1.60) | Quartile 2 (1.60–2.20) | Quartile 3 (2.20–3.11) | Quartile 4 (≥3.11) | P for trend |
Median, mg/mL | 1.18 | 1.86 | 2.46 | 4.00 | |
Cases, n | 115 | 140 | 191 | 206 | |
Incident rate | 17.32 | 21.64 | 24.87 | 29.68 | |
OR (95% CI) | | | | | |
Multivariable model 1 | Ref. | 1.38 (1.13, 2.79) | 1.63 (1.35, 3.38) | 2.30 (1.62, 4.25) | ༜0.001 |
Multivariable model 2 | Ref. | 1.16 (1.01, 1.59) | 1.43 (1.07, 2.56) | 1.91 (1.09, 3.35) | 0.002 |
Multivariable model 3 | Ref. | 1.09 (1.04, 1.15) | 1.34 (1.06, 2.65) | 1.83 (1.10, 3.38) | 0.015 |
Multivariable model 1 adjusted for age and BMI; Multivariable model 2 adjusted for the variables in Model 1 plus smoking and drinking status, education background, systolic blood pressure, diastolic blood pressure, TC, TGs, LDL-C and HDL-C. Multivariable model 3 adjusted for the variables in Model 2 plus ALT, AST, uric acid, total bilirubin, direct bilirubin, urea nitrogen and creatinine. PY, person-year; Ref., referent. |
Significant difference if P < 0.05 |
Next, we assessed the predictive values of bile acids for GDM. As displayed in Fig. 2, the similar Area under the curve (AUC) existed in the TBA model (AUC: 0.66, 95% CI: 0.63–0.68) and the traditional risk factor model (AUC: 0.68, 95% CI: 0.66–0.70). After including TBA in the traditional risk factor model, the AUC markedly increased (AUC: 0.72, 95%CI: 0.68–0.76) (P < 0.001).
Table 4
Adjusted odds ratios (95% confidence intervals) of adverse outcomes according serum TBA quartiles.
Outcomes | | TBA (µmol/L) |
| | Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 | P for trend |
(< 1.60) | (1.60–2.20) | (2.20–3.11) | (≥3.11) |
Preterm birth | Model 1 | Ref. | 1.16 (0.70, 1.77) | 1.43 (0.80, 2.56) | 1.94 (1.09, 3.35) | 0.005 |
| Model 2 | Ref. | 1.09 (0.75, 1.28) | 1.14 (0.71, 1.84) | 1.91 (1.26, 2.98) | 0.017 |
PROM | Model 1 | Ref. | 0.98 (0.63, 1.41) | 1.15 (0.38, 1.84) | 1.71 (0.41, 3.78) | 0.248 |
| Model 2 | Ref. | 0.89 (0.69, 1.14) | 1.02 (0.46, 1.78) | 1.65 (0.51, 2.83) | 0.347 |
Preeclampsia | Model 1 | Ref. | 1.17 (0.33, 2.63) | 1.48 (0.55, 3.27) | 2.28 (0.87, 4.91) | ༜0.001 |
| Model 2 | Ref. | 1.10 (0.54, 1.67) | 1.34 (0.83, 2.63) | 2.07 (1.19, 3.63) | 0.002 |
Macrosomia | Model 1 | Ref. | 1.28 (0.81, 1.92) | 1.19 (0.79, 1.79) | 1.15 (0.75, 1.76) | 0.781 |
| Model 2 | Ref. | 1.22 (0.80, 1.88) | 1.15 (0.76, 1.74) | 1.09 (0.71, 1.67) | 0.822 |
Model without adjustment. |
Model 2 adjusted for the variables of age, BMI, smoking and drinking status, education background, systolic blood pressure, diastolic blood pressure, TC, TGs, LDL-C, HDL-C, ALT, AST, uric acid, total bilirubin, direct bilirubin, urea nitrogen and creatinine. Ref., referent. |
GDM, gestational diabetes mellitus; TBA, total bile acid; PROM, premature rupture of membranes. |
Significant difference if P < 0.05 |
Association between serum TBA levels and adverse perinatal outcomes in women
We next further identified whether TBA levels responsible for the adverse perinatal outcomes in women. We performed binary logistic regression with the first quartile of serum TBA levels (< 1.60 µmol/L) as a reference. We found that a higher serum TBA level was associated with higher odds of preterm birth (the highest quartile vs. the lowest quartile, AOR 1.91, 95% CI 1.26–2.98, P-trend = 0.017) and preeclampsia (the highest quartile vs. the lowest quartile, AOR 2.07, 95% CI 1.19–3.63, P-trend = 0.002). No linear association was detected between TBA and PROM or macrosomia (P > 0.05) (Table 4). In Fig. 3, we used restricted cubic splines to flexibly model and visualize the non-linear relation of TBA with the risk of PROM and macrosomia. Regarding the U-shaped relation between TBA and PROM, the plot showed a substantial increased risk within the low range of TBA, which reached the lowest risk for PROM around 3.14 µmol/L, and then increased thereafter (All P-nonlinear < 0.01).